Before the present invention, radiation delivery in the bone marrow transplant setting has depended upon the clinical indication. When treating marrow-based diseases by a marrow transplant, irradiation has been delivered almost solely by external beam total body irradiation (TBI). Attempts to improve the rate of eradication of malignant cells by increasing the dose of radiation delivered have generally been limited by toxicity to normal organs such as lung or liver.
Marrow transplants in which the main goal is marrow ablation (rather than eradication of a malignancy) have used either TBI with chemotherapy, or a chemotherapy-only regimen. In either case, the therapy is not delivered specifically to sites of disease, but is instead given systemically, and each type of regimen has potential toxicities to normal organs. The ability to avoid exposing the lung and liver to high doses of irradiation and/or chemotherapy, while delivering adequate doses to marrow and lymphoid tissue, would allow transplants for these conditions to be performed with less risk to the patient.
Immunosuppression in the marrow transplant setting has generally been achieved by TBI/chemotherapy, or chemotherapy-only regimens, which again have a high rate of toxicity to normal organs. In some cases, such as mismatched or T-cell depleted marrow transplants, even the usual TBI-containing regimens frequently fail to achieve adequate immunosuppression and graft rejection occurs in an unacceptably high number of patients. The delivery of additional "total lymphoid irradiation" (TLI) by directed external beam radiotherapy has increased the degree of immunosuppression but its use has been limited by toxicity to neighboring tissues, particularly the mucosa of the mouth, oropharynx, and esophagus.
In summary, although in general higher doses of irradiation have led to decreased rates of relapse and enhanced immunosuppression, this has not translated to improved survival because of the accompanying severe regimen-related toxicity when this irradiation is delivered via traditional, external beam sources (TBI or TLI).
In general, most previous reported attempts to destroy malignant or otherwise undesirable cells with a targeted "magic bullet" approach have purposefully used monoclonal antibodies which are as "tumor specific" as possible. For example, in experimental studies of radiolabeled antibody therapy of lymphoma, the present inventors have tested the theoretically most "tumor-specific" reagent possible, which is an antibody reactive with the "idiotypic determinant" which is specific to the immunoglobulin molecule expressed only by the cells of the lymphoma itself (that is, not by normal lymphocytes). Alternatively, they have tested the approach of targeting an antigen present on most B cells, including the lymphoma cells. This is, in a sense, "one step less specific" than the anti-idiotype antibodies. In this case, the selection of a pan-B reactive antibody is one of convenience, in that such an antibody reacts with most lymphomas (and therefore need not be tailor-made for each patient), yet still is relatively tumor-specific; the reactivity with normal nonlymphomatous B cells is accepted although such cells are not the primary target. Other clinical trials of targeted radiotherapy using monoclonal antibodies have also generally employed antibodies which are as tumor-specific as possible, accepting nontumor reactivity as an unavoidable side effect.